Benzhydryl ethers of alkyl piperidinols



United States Patent @fiice 2,745,837 hatented May 15 1956.

ALKYL PIPERIDINGLS Donreni'clPaPaiand stephen-B. Coan; Bloomfield, N.J., a's'si'gnors-to=Scheri;ng CorpbratiomBloomfield, N. J'., acorporation:- ofiNew Jersey N Drawing. ApplicationJanuary 21,1954,Serial'No. 405,495

Claims.- (Cl. 250-4945) This invention r'elates' to a new group ofcompounds I: R4 I wherein R1 and R2 are members of the group comprisinghydrogen,- halogen, lower alkyl and lower alkoxy radicals, RsrepresentszH. and lower alkyl, Rtzis a'member of the. group comprisinglower alkyl and-monocyclic arailiylQX isa member: of. the groupconsisting of O and S, Y is al ovver alkyl group and n is-an integerfrom l'4.

We have found that the compounds of this invention, which unlike manycompounds in clinical use, exhibit prolonged antihistamine" efiec't'aswell as substantial anticholinergic'properties. Furthermore,.\ve havefound that these" compounds exhibit a marked enhancement of actionininhibiting gastrointestinal motility: and also possess anestheticproperties. These properties are' exhibited to a greater degree by thefree bases and the acid-addition salts thereof, with the ethers of the4-piperidinols being most active.-

The compounds of this invention may generally be prepared by' reacting apiperidinol with a benzhydryl halide in the presence of a basic catalystandif'd'esired, an inert solvents'uch' as toluene or Xylene.Specifically, when benzliydryl bromide is refluxed withl,2,'2,6-tetramethyl-4-piperidinol in an;hydrous-xylene in the presenceof anhydrous potassium-carbonate, there is-obtained the benzhyd'rylether of 1,2,2,6 tetramethyl-4-piperidinol.

Although the'compoundsof our invention may be'prepared by simplyheating. the desired reactants together until "the desiredether isobtained; we-preferto carry out the reaction in the presence of someinert solvent such as an aliphatic or aromatic hydrocarbon or highboiling ether. The particular solvent is not critical since its primary"purpose is to permit moreeflicient interaction of the reactants. Thusany nnreactive solvent-having a boiling point above 8'0 may be employed.

Inthis reaction, a mole of hyd rohalic' acid is liberated and"since itmayprecipitate the ether or even some unreacted basic alcohol, we preferto employ an acidacceptor suchas pyridine, diallcylanilines or.asshown/above, inorganic bases such: as sodium or potassium carbonate.A1ternatively,,an excess of basic alcohol-may housed: to neutralize thehydrogen halide released, In those cases wherein the basic alcohol isliquid: atthereactiontemperature, it may be employed assolventt.

The reaction is preferably carried outmore' or less under anhydrousconditions in order to realize more favorableyields; therefore it is.preferable to. employ only substantially anhydrous reactants andsolvents.

In addition to the foregoingthe: appropriate piper-idinol may bealkylated with a suitable benzhydryl halide-in liquid ammonia solventusing. an alkali. metal: amideas catalyst. For example,reacting1,2,6-trimethyll4-piperh dinol with p-chlorobenzhydrylchloride:in.liquidammonia in the presence of sodamide, yields1,2,6-tn'rnethyl-4- piperidyl p-chlorobenzhydryl ether.

The intermediate alkyl'ated'piperidinols areeasily prepared bymethodswellknown to those sltilled intthe art. According to Campbell eta1. 3*.- Org. Chem. 15;. 337 (1950) v-pyrones' react with ammonia andalky-l amines to give the analogous pyridone which, uponreduction withhydrogen at elevated temperatures. and pressure in the presence of acatalyst, such asRaney nickel, yielding the desired 4-piperidinol.Thusl;2,6-'tr-imethyl-f4-piperi= dinol' is prepared by reacting2.,6=dimethyl: -pyrone with methylamine and catalyticaily reducing thepyridonewith hydrogen. This method is'applicable tothe preparation of1-benz-yl-4-piperidinol-'byusingammonia in place of the methylamine andafter reduction, theA-hyd'roxypiperidine is alkylated with benzylchloride.

Instead of utilizing the 'y-pyro'nes or ring closure pro cedures, thepiperidinol's may be prepared from pyridine compounds. For example;reduction of Z-methyl-S-nitropyridinewithhydrogen-in thev presence'iof acatalyst such as platinum" oxide, affords 2-nethyl 5 aminopyridinewhich, upon diazotization andhydrolysis, results in the formation 05Z-methyl-S-pyridb'l. Qnaternization of the pyridol' wim-dimethylsulfate,for example; followed by reduction with hydrogen'in the presence-ofplatinum oxide yields 1,Z-dimethyl-S-hydroXy-piperidinei Alternatively,2-methyl-5-pyridol may be reduced at elevated temperatures and pressuresusing Raney nickel catalyst and the resultant.hydroxypiperidinealkylated to suit. For example, ifthe N rn'e'thylated compound isdesired, formaldehyde and formic acid may conveniently be employed to"give' l,2 dimethyl 5-piperidinol. It is apparentto one sltilled'intheart that various modiiica tions of suchprocedures may be employed toprepare intermediates used in this invention.

Toprepare compounds of general. Fonn'ula: I" wherein X issulfur, thecorresponding thiopiperidine may be e'm ployed. The interme iatethiopiperidines are preferably obtained from the reaction of. apiperidinol with an agent such as phosphorous pentasulfidea The purifiedthiols are then subjected to the-same type of reaction as their oxygenanalogs. For example, heatinganintimate mixture of1,2,6-trimethy1-4-piperidinol and. phosphorous pentasulfide followed bydistillation after the excess sulfurizing agent is-destroyed, affordsthe corresponding 1,2,fi-trimethyh i-diiopiperidine.

The non-toxic acid addition salts of the basic ethersand thioethers ofgeneral Formula I are prepared by reacting the basic ether or thioetherdirectly with an acid in. the usual manner, preferably in the presenceof a solvent. For example, by passing anhydrous hydrogen chloridethrough an ether solution or" l,2,2,6-tetramethyl-4-piperiand refluxedovernight.

25 dinol, there precipitates the corresponding hydrochloride which maybe recrystallized from alcohol-ether. Similarly by heating theaforementioned base with an equivalent of maleic acid in isopropylacetate, for instance, the corresponding maleic acid salt is obtainedupon cooling. Examples of non-toxic anions which may be employed arechloride, bromide, maleate, tartrate, citrate and the like.

The quaternary salts of the free bases of this invention may be preparedby reacting the base with an alkyl halide or sulfate such as methylbromide and the like, optionally in the presence of an inert solvent.Alternatively, quaternary chlorides and bromides may be prepared fromthe corresponding iodides by heating an alcoholic solution of the iodidein the presence of a silver halide whereupon halogen exchange isefiected.

The compounds of the present invention may be administered in a varietyof pharmaceutical forms such as tablets, capsules, elixers and the like.They may be dissolved or suspended in non-toxic vehicles which may beflavored to suit so as to make the medicament palatable.

The following examples illustrate the preparation of the compounds ofthis invention, but do not limit invention except as defined in theappended claims.

EXAMPLE I 1,2,2,6-tetramethyl-4-piperidyl benzhydryl ether A mixture of24.0 g. of l,2,2,6-tetramethyl-4-piperidinol, 11 g. of anhydrouspotassium carbonate, 37 g. of benzhydryl bromide in 100 ml. of xylene isstirred After cooling, the mixture is poured into water and extractedwith ether. The ether solution is extracted with dilute aqueoushydrochloric acid and the acid solution, after treatment with dilutesodium hydroxide solution, is extracted with ether. The ether solutionis washed with water, dried over anhydrous potassium carbonate,concentrated in vacuo and distilled to yield1,2,2,6-tetramethyl-4-piperidyl benzhydryl ether, B. P. l78-180/3-4 mm.

EXAMPLE II I,2,2,6-tetramethyl-4-pipefldyl benzhydryl ether methiodide Asolution of 7 g. of the amino-ether of Example I, 25 g. of methyl iodideand 100 ml. of anhydrous ether is refluxed for 3 hours and allowed tostand overnight. The mixture is cooled, filtered and the crystals soobtained recrystallized from aqueous alcohol, yielding1,2,2,6-tetramethyl-4-piperidyl benzhydryl ether methiodide, M. P.260.8-26l.

EXAMPLE IH 1,2,2,6-tetramethyl-4-piperidyl benzhydryl ether maleate Therequisite intermediate, silver bromide, is freshly prepared as follows:

A solution of 0.05 mole of silver nitrate in 100 ml. of water is treatedwith a slight excess of aqueous hydrobromic acid. The resultant mixtureis warmed until the precipitate coagulates. The silver bromide isremoved by filtration and washed thoroughly with water and then withmethanol, keeping the salt moist throughout the operation.

To a stirred suspension of the freshly prepared silver rornide, in 300ml. of anhydrous methanol, is added a solution of 0.03 mole of thequaternary iodide obtained in Example 11. The mixture is stirred andrefluxed overnight whereupon, after cooling, the suspended salts areremoved by filtration. Evaporation of the methanolic solution followedby recrystallization of the residue from methanol-ether yields thequaternary bromide of this example.

- EXAMPLEV I,2,2,6-tetramethyl-4-piperidyl p-chlorobenzhydryl ether To astirred mixture of 23.7 g. of l,2,2,6-tetramethyl-4-piperidinol, 11 g.of anhydrous potassium carbonate in ml. of xylene, is slowly added asolution of 42 g. of p-chlorobenzhydryl bromide in 50 ml. of xylene; Thereaction mixture is processed as described in Example I, yieldingl,2,2,6-tetramethy1-4-piperidyl p-chlorobenzhydryl ether, B. P. l93/lmm.

EXAMPLE VI J,2,2,6-tetramethyl-4-piperidyl p-chlorobenzhydryl methiodideA solution of 8 g. of the amino ether of Example V, 20 ml. of methyliodide, 50 ml. of anhydrous ether is refluxed for 3 hours and allowed tostand overnight. The quaternary salt which precipitates is removed byfiltration and recrystallized from aqueous-ethanol, M. P. 238239.4.

H EXAMPLE VII J,2,6-trimethyl-4-piperidyl a,oz-diphenylethyl ether Fromthe reaction of 1,2,6-trimethyl-4-piperidinol and 1,1-diphenylethylbromide, according to the procedure of Example I, there is obtained1,2,6-trimethyl-4-piperidyl a,a-diphenylethyl ether, B. P. l75180/ 3 mm.

EXAMPLE VIII 1,2,2,6-tetramethyl-4-piperidyl p-methylbenzhydryl ether Bysubstituting p-methylbenzhydryl bromide in the procedure described inExample V, there is obtained 1,2,12,6- tetramethyl-4-piperidylp-methylbenzhydryl ether, B. P. l90195/2 mm.

EXAMPLE DC 1,6-dimethyl-3-piperidyl benzhydryl ether By treating1,6-dimethyl-3-piperidinol with benzhydryl bromide according to theprocedure of Example I, there is obtained 1,6-dimethyl-3-piperidylbenzhydryl ether, B. P. 172/1 mm.

EXAMPLE X 1,6-dimethyl-3-piperidyl benzhydryl ether methiodide From thereaction of the amino-ether of Example IX with methyl iodide accordingto the procedure of Example II, there is obtained1,6-dimethyl-3-piperidyl benzhydryl ether methiodide.

EXAMPLE XI 1,2,6-trimethyl-S-piperidyl benzhydryl ether By reactingequimolar quantities of 1,2,6-trimethyl- B-piperidinol with benzhydrylbromide according to the procedure of Example I, there is obtained1,2,6-trimethyl- S-piperidyl benzhydryl ether, B. P. 180/1 mm.

EXAMPLE )QI 1,2,6-trimethyl-.i-piperidyl benzhydryl ether methiodide Bysubstituting the amino-ether of Example XI in the procedure described inExample II, there is obtained 1,2,6-trimethyl-3-piperidyl benzhydrylether methiodide, M. P. 272.5-273.5.

EXAMPLE XHI 1,2,6-trimethyl-4-piperidyl benzhydryl thioether Therequisite intermediate, 1,2,6-trimethyl-4-thiopiperidine is prepared asfollows:

An intimate mixture of equimolar quantities of 1,2,6-

trimethyl t piperidinol" and phosphorous" penta'suliiide is heated at150-200 for several hours. After cooling;

1,2,6-trimethyl-4-piperidyl benzhydryl ether 7 From the reaction of 21.5g. of l,2,6-t1imethyl-4-piperidinol, 11 g. of anhydrous potassiumcarbonate, 37 g. of benzhydryl bromide in 150 ml. of anhydrous xyleneaccording to the procedure of Example I, there is obtained the ether ofthis example, B. P. l86l9l/34 mm.

EXAMPLE XV 1,2,2,6-tetramethyl-4-pipefidyl p-methylbenzhydryl ether Fromthe reaction of 23.7 g. of 1,2,2,6-tetramethyl-4-piperdinol, 11 g. ofanhydrous potassium carbonate, 39.1 g. of p-methylbenzhydryl in 150 ml.of anhydrous xylene according to the procedure of Example I, there isobtained the above-entitled ether as a clear viscous oil, B. P.211-212/34 mm.

EXAMPLE XVI 1,2,2,6-tetramethyl-4-piperidyl pp'-dichlor0benzhydryl etherBy substituting pp'-dichlorobenzhydryl bromide in the proceduredescribed in Example I, there is obtained the above-entitleddichlorobenzhydryl ether, B. P. 225- 230/ 1 mm.

EXAMPLE XVII 1,2,6-trimethyl-3-piperidyl pp'-dimethylbenzhydryl ether Byreacting equimolar quantities of 1,2,6-trimethyl-3- piperidinol withpp'-dimethylbenzhydryl bromide according to the procedure of Example I,there is obtained the compound of this example, B. P. 210-215 /0.5 mm.

EXAMPLE XVIII 1,2,6-trimethyl-4-piperidyl pp'-dimethoxybenzhydryl etherFrom the reaction of 1,2,6-trimethyl-4-pipc1idinol withpp-dimethoxybenzhydryl bromide according to the procedure of Example I,there is obtained 1,2,6-t11'methyl-4- piperidyl pp'-dimethoxybenzhydrylether, B. P. 240- EXAMPLE XIX 1-ethyl-2,6-dimethyl-4-piperidylbenzhydryl ether By reacting equimolar quantities of1-ethyl-2,6-dimethyl-4-piperidinol with benzhydryl bromide according tothe procedure of Example I, there is obtained l-ethyl-2,6-dimethyl-4-piperidyl benzhydryl ether, B. P. 185- l90/ 3-4 mm.

EXAMPLE XX 1-benzyl-2,6-dimethyl-4-piperidyl benzhydryl ether v i;liydroxide may be used; In addition to theforegoinggthe followinexamples show alternatenietliods of preparing the compounds of thisinvention.

EXAMPLE XXI:

1;2',6#trimethyl 3-piperidyl'm=bromolienzliydryl ether To a suspensionof 0.1 mole.ofi sodamide in SOQ :ml.- of anhydrous toluene is added asolution of 0.1 mole ohm. bromobenzhydrol in toluene. The mixture isrefluxed for several hours, after which time a solution of 0.1 mole of1,2,6-trimethyl-3-chloropiperidine (prepared according to the procedureof Fuson and Zirkle, J. A. C. S. 70, 2760 (1948) is slowly added. Thereaction mixture is re fluxed for an additional 4 hours and, aftercooling, is poured into ice-water and extracted with ether. Followingthe isolation procedure of Example I, there is obtained thebromobenzhydryl ether of this example, B. P. l-l95/ 1 mm.

Alternatively, the compound of this example is prepared fromm-brombenzhydryl bromide and 1,2,6-tiimethyl-3-piperidinol, according tothe procedure of Example I.

EXAMPLE XXII 1,2,6-trimethyl-4-piperidyl p-methyl-p -chlorobenzhydrylether A mixture of 0.1 mole of potassium hydroxide in toluene isdistilled until all of the water is removed azeotropically. To thestirred, refluxing mixture is added 0.1 mole ofm-methyl-m-chlorobenzhydrol and the resulting mixture refluxed forseveral hours, at which time 0.1 mole of1,2,6-trimethyl-4-chlo1piperidine in anhydrous toluene is added slowlyand the reaction mixture is refluxed overnight. The mixture is cooled,poured into ice-water and extracted with ether and, following theisolation procedure of Example I, the benzhydryl ether of this exampleis obtained as a viscous oil, B. P. 230- 235 0.5 mm.

Alternatively, the compound of this example is prepared from m-methyl-m-chlorobenzhydryl bromide and 1,2,6-trimethyl-4-piperidinol, followingthe procedure of Example I.

EXAMPLE XXIII 1,2,6-trimethyl-4-piperidyl u-p-tolyl-a-phenylethyl etherTo a suspension of 0.1 atom of powdered sodium in ml. of anhydroustoluene is slowly added a solution of 0.1 mole of1,2,6-trimethyl-4-piperidinol in 100 ml. of anhydrous toluene. Themixture is stirred and refluxed for several hours until the aminoalcohol is completely converted to its sodium salt. To the cooled,stirred suspension of the sodio derivative there is slowly added asolution of 0.1 mole of u-p-tolyl-a-phenylethyl bromide. The resultingmixture is refluxed for several hours and, after cooling is poured intoice-water and extracted with ether. The ether solution is extracted withdilute aqueous hydrochloric acid and the acid solution is made alkalinewith dilute sodium hydroxide solution. The aqueous alkaline mixture isextracted with ether and the ether extracts dried with anhydrouspotassium carbonate, concentrated in vacuo, and distilled to yield thecompound of this example, B. P. l80185/l mm.

We claim:

1. Compounds of the group consisting of bases of the general formula:

ether.

ether.

4. 1,2,2,6-tetramethy1-4-piperidy1 p-methylbenzhyd ryl ether.

5. 1,2,6 -trimethyl-3-piperidy1 p,p ,-c1imethy1benzhydryI ReferencesCited tn the file of this patent UNITED STATES PATENTS Rieveschl, Jr.Nov. 16, 1948 I Knox Aug. 23, 1949

1. COMPOUNDS OF THE GROUP CONSISTING OF BASES OF THE GENERAL FORMULA: